What Is the Future of Thiazolidinediones (TZDs) After Market Introduction of Inhaled Insulin?

The U.S. Food and Drug Administration (FDA) approved inhaled insulin (INH) under the trade name Exubera on January 27, 2006, for use in adult patients with type 1 and type 2 diabetes. Exubera is an inhalable, powdered form of insulin delivered by a device developed by Nektar Therapeutics. Earlier in January 2006, Pfizer agreed to acquire the world-wide rights to Exubera from sanofi-aventis for $1.3 billion.

affirms our intuition that (a) patients can discern among specific sensory attributes of intranasal steroid products, (b) some attributes have higher economic value in their avoidance (e.g., no aftertaste versus strong aftertaste), and (c) the absolute WTP amount is higher for some attributes (i.e., a lot of throat rundown and nose runout) for persons with higher household income. It may also be reasonable to extrapolate these findings to the conclusion that physicians and patients should be discussing product attributes, particularly for patients who will be using intranasal steroids on a regular basis due to persistent symptoms.
The implications of the research on WTP for sensory attributes beyond these conclusions are less clear. The graphs (Figure 1) in the article by Mahadevia et al. are remarkably similar in slope and clustering except for aftertaste ( Figure 1C). Second, at $50 per prescription, the sensory attributes have little differentiation. (Readers are encouraged to examine the Choice Set in Table 3 of the article to make their own inferences.) Based upon the actual costs of the 7 therapeutic alternatives in 2005 (Table 1 page 168), there is only an absolute difference of $5 per month between budesonide, mometasone, triamcinolone, and fluticasone.
Members of pharmacy and therapeutics (P&T) committees are challenged in decision making by the absence of information about sensory attributes in the labeling for intranasal steroids. But, Kaliner found, in a telephone survey of 503 patients with seasonal and perennial allergic rhinitis, that 86% of the patients reported that they had not complained to their physician about a sensory attribute of their nasal steroid treatment. 13 Since the work by Kaliner was performed 6 years ago, this research, if conducted today, may find that patients are more outspoken. On the other hand, perhaps sensory attributes of intranasal steroids are important to only a small proportion of the population that suffers from allergic rhinitis. One wonders how important the sensory attributes of intranasal steroids should be in clinical and P&T committee decision making. The one apparent opportunity for quality improvement is in increasing, to more than 7%, the proportion of physicians that base their choice of a nasal steroid on patient preference 14 for sensory attributes.  15 Exubera is an inhalable, powdered form of insulin delivered by a device developed by Nektar Therapeutics. Earlier in January 2006, Pfizer agreed to acquire the world-wide rights to Exubera from sanofi-aventis for $1.3 billion. 16 One of the clinical trials that favored FDA approval of INH was a multicenter clinical trial that randomized 145 persons with uncontrolled type 2 diabetes (with glycosylated hemoglobin [A1c] in the range of 8%-11%) to either INH before meals or rosiglitazone (Avandia) 4 mg twice daily. 17  Pharmacy and therapeutics (P&T) committees have an interesting question to debate in 2006: the relative value and need for the thiazolidinediones (TZDs) rosiglitazone (Avandia and Avandamet) and pioglitazone (Actos) now that clinicians and patients have access to INH, which has been found to be superior to rosiglitazone in the intermediate outcome of A1c. TZDs have a larger hole to crawl out of when relative safety is considered by P&T committees and clinicians. More than 2 years ago, at the end of 2003, the American Heart Association and the American Diabetes Association released a joint consensus statement warning that patients with moderate-to-severe congestive heart failure (CHF) should not be prescribed either rosiglitazone or pioglitazone. 19 Analysis of administrative claims data reported in November 2003 by Delea found a 55% higher incidence of heart failure for 5,441 TZD patients compared with 28,103 control patients with diabetes (hazard ratio = 1.7, P <0.001); the adjusted incidence of heart failure at 40 months was 8.2% for TZD patients and 5.3% for control subjects (absolute difference 2.9%, relative difference 55%). 20 The TZDs have a tendency to cause fluid retention and edema, particularly of the feet, a hallmark of CHF. The incidence of fluid retention and edema appear to be exacerbated by concomitant use of insulin and dose-related for both rosiglitazone 21 and pioglitazone. 22,23 The black cloud over TZDs does not end with fluid retention, edema, and heart failure. The first TZD, troglitzone (Rezulin), approved by the FDA for marketing in the Unites States in January 27, 1997, 24 was withdrawn in March 2000 after its association with hepatotoxicity was no longer in doubt. By year-end 1998, the FDA had record of a total of 32 reported deaths and 4 liver transplants associated with the use of troglitzone. 25 Prior to the market withdrawal of troglitazone, the manufacturer had distributed 2 warning letters to physicians, including a notice to monitor liver enzymes monthly, and the United Kingdom had withdrawn troglitazone from the market more than 2 years earlier, in November 1999. 26 For pioglitazone, introduced to the U.S. market in July 1999, 27 the first death from liver failure associated with its use was reported in 2004. 28 A "Dear Prescriber" letter dated April 26, 2002, highlighted changes in the precautions section of labeling of rosiglitazone regarding the potential for hepatic effects, even a rare case of hepatic failure, and, in other parts of product labeling, a possibility of weight gain.
Add to peripheral edema, weight gain, and possible hepatotoxicity an apparent increased risk of macular edema. In January 2006, the FDA notified health care professionals of reports of both new-onset and worsening cases of diabetic macular edema associated with the use of rosiglitazone, albeit reversible and apparently dose related. 29 With an apparent black eye for safety and inferior to INH in efficacy for lowering A1c, the cost outcomes for the TZDs may offer a refuge in the storm. Kalsekar et al., in this issue of JMCP, found, from administrative claims data in a Medicaid fee-forservice population, that patients who started TZD therapy incurred 35% lower costs in a 12-month follow-up period in 2000-2001 for emergency room (ER) visits and hospitalization compared with patients who initiated therapy with insulin, an average of $3,727 versus $5,793, respectively (P <0.01). 30 For diabetes-related costs only, the 53% higher pharmacy costs in the TZD patients ($1,678) versus insulin patients ($1,096, P <0.01) was offset by lower costs for emergency room (ER) visits and hospitalization ($2,855 vs. $5,090, P <0.01), resulting in 25% lower total diabetes-related costs for the TZD group compared with the insulin group ($5,425 vs. $7,255, P <0.05).
Limitations in the study by Kalsekar et al. are significant. Important among these limitations was the inability to measure disease severity. Lacking clinical values for A1c and blood glucose, the researchers attempted to assure the comparability of the 2 groups through the use of propensity matching. However, the propensity matching technique would tend to exclude patients with more-severe diabetes who were, therefore, using insulin and could not be matched to TZD patients. The magnitude of this limitation can be gleaned from the authors' Table 1, which shows that 65% (n = 1,271) of otherwise studyeligible patients were excluded in the process of propensity matching, leaving only 690 patients in the final analyses: 345 patients with type 2 diabetes in the TZD group and 345 patients in the insulin group.
Second, Medicaid patients, particularly those not enrolled in managed Medicaid, are most likely not representative of the general population of patients with type 2 diabetes, and discontinuous eligibility contributes to discontinuous care in this population. 31 A hint of the problem of discontinuous care might be found in the 75% of patients identified with a diagnosis of type 2 diabetes who were excluded from the study because of the absence of a pharmacy claim for TZD or insulin plus another 12% of patients who did not have continuous eligibility during the study period. LaFleur, in a previous issue of JMCP, provided a comprehensive and useful review of the limitations of administrative claims data specific to the measurement of costs of care for patients with type 2 diabetes. 32 Third, the time period for the administrative claims used in the analyses by Kalsekar et al. is confounded by the TZD market disruption caused by the withdrawal of troglitazone in March 2000, in the middle of their 1999-2001 study period. While troglitazone patients were excluded from the 12-month followup period, 12.8% of the TZD patients and 13.0% of the insulin patients in the final analysis received troglitazone in the preperiod ( Table 3 in Kalsekar et al.). One wonders why the outpatient costs, which included office visits and laboratory tests for liver enzymes, were not higher in the preperiod for both groups and why the outpatient costs were similar ($177 mean difference, $1,070 for the insulin group compared with $893 for the TZD group, P = 0.458 for the comparison) in the postperiod, particularly since there was considerable media attention to the market withdrawal of troglitazone at the time. Consumer groups, represented by Public Citizen, petitioned the FDA in early 2000 to revise the product labeling for all 3 TZDs to describe the adverse effects that include liver toxicity and heart failure. 33 Fourth, a threat to validity seems inherent in the premise that higher drug costs for TZDs are offset by lower costs for ER visits and hospitalizations, in only 12 months of administrative claims data. For diabetes-related costs, the insulin group had a higher average number of physician office visits, but the average outpatient costs (including physician office visits) were not different between the 2 groups over 12 months of follow-up. However, the contribution of the $177 mean difference ($1,070 for the insulin group vs. $893 for the TZD group, P = 0.458 for the comparison) may have contributed to the $1,830 difference ($153 per month) in total diabetes-related costs ($7,255 for the insulin group vs. $5,425, P = 0.022 for the comparison).
Stephens et al. provide a useful context for interpreting these absolute and relative values in their summary of the literature on economic studies in this issue of JMCP, including their Table 1, showing the breakdown of total direct costs for managed care organization (MCO) enrollees with diabetes. 34 The place in therapy for TZDs in type 2 diabetes is summarized clearly and succinctly in the NICE (National Institute for Clinical Excellence) appraisal released in November 2002. TZDs are third-line therapy in type 2 diabetes after sulfonylureas and metformin have proved unsuccessful when used as monotherapy and in combination to achieve glycemic goals. 35 NICE concluded that "the use of glitazone combination therapy with either metformin or sulphonylurea is not likely to be cost effective when compared with the combination of metformin and sulphonylurea." So, much of the market future of TZDs may have to do with